One of the serious consequences of chronic alcohol use is the development of physical dependence and the possibility of experiencing a life- threatening withdrawal syndrome. A variety of pharmacologic agents have been used for the medical management of ethanol (EtOH) withdrawal. However, while a great deal of effort has focused on evaluating treatment of a single withdrawal episode, very little attention has been directed toward the potential impact of multiple EtOH withdrawal experiences on treatment efficacy, as well as choice of treatment. This is particularly relevant given the high rate of recidivism among alcoholics, along with the fact that many alcoholic patients presenting for treatment have a history of numerous prior detoxification experiences. Accordingly, this proposal is focused on evaluating pharmacotherapy for multiple EtOH withdrawals. We have recently established an animal model of EtOH withdrawal that demonstrates the potentiating effects of prior EtOH withdrawal experiences. This, along with other experimental and clinical evidence provide support for the kindling hypothesis of alcohol withdrawal. While much of this work has focused on the progressive intensification of physical symptoms of withdrawal (seizures), it would seem that effective treatment needs to also target the psychological (anxiety) and subjective perception of EtOH cues) components of the withdrawal syndrome, given the potential importance of these variables in the motivation to resume drinking. The proposed work will use an established model of multiple EtOH withdrawals to evaluate the efficacy of various pharmacotherapies in treating physical as well as psychological and subjective aspects of the withdrawal syndrome. While elucidation of mechanisms is not the primary goal of this clinically- oriented project, relevant basic research findings have provided guidance and a rationale for the selection of drugs to be evaluated. More specifically, we have chosen to initially focus our investigation on drugs active at the GABAa, glutamate (NMDA and non-NMDA), and voltage-operated calcium channel receptor systems. The effects of non-sedative anticonvulsants will be examined as well. These drugs have been selected because they target neurochemical systems that (a) exhibit neuroadaptive changes to chronic EtOH exposure which may underlie EtOH withdrawal symptoms and (b) are involved in neuronal plasticity events (which may be akin to the kindling process). Thus, these drugs may be particularly appropriate with regard to treatment for patients with a history of multiple EtOH withdrawals. Taken together, the proposed work may provide important clinically-relevant information regarding more effective pharmacotherapy strategies for treating acute EtOH withdrawal, as well as long-term management of EtOH dependence and alcoholism.